Tumors frequently enlist developmental genes to translate oncogenic signals into drivers of tumor progression. To gain a better understanding of the molecular mechanisms behind lung carcinogenesis and progression, we are focusing on the potential role of Sox9, a transcription factor required for human development. We found that Sox9 is barely expressed in normal lung tissue, but is overexpressed in primary human and murine lung tumors as well as lung cancer cell lines. We determined that Sox9 is not only a direct target gene of Notch1 signaling, but it is also a key mediator of Notch1-induced mesenchymal-like cellular morphological changes, E- cadherin repression, cell motility, and invasion in lung cancer. Our studies suggest that Sox9 is downstream of other oncogenic pathways. We propose that Sox9 is a terminal hub for convergence of upstream oncogenic signals, and plays a central role in mediating their contribution to lung tumorigenesis and progression. Therefore, targeting Sox9 expression could alleviate the resistance often invoked by redundant oncogenic pathways during treatment with targeted therapies. The overall goals of this proposal are to validate the pathways regulating Sox9 expression and mediating Sox9's role in the induction of cell motility and invasion. We will test the function of Sox9 during murine lun carcinogenesis. Using patient-derived lung tumor xenografts and a validated platform to target Sox9 in vivo, we will test if Sox9 repression has anti-tumor activity. This study will help in understanding the regulation of lung tumor progression by a novel embryonic developmental gene and develop a strategy for potentially circumventing therapeutic resistance.